Persistent viral infections are a worldwide health concern, with over 500 million people infected with HIV and hepatitis B and C viruses (HBV, HCV). By definition, immune escape is required for viral persistence;however the suppressive mechanisms that abort immunity during persistent viral infections are not well defined. T cell responses are crucial to prevent and control viral infections. Although robust T cell responses are initially mounted to these viruses, T cells rapidly lose activity permitting persistence. Recent evidence suggests that the functionally non-responsive T cell state (exhaustion) is not programmed during T cell activation, but that T cell responses are actively suppressed throughout infection. We discovered that infection with a persistent strain of lymphocytic choriomeningitis virus (LCMV) triggers high IL-10 production that directly ablates T cell function and causes viral persistence. Antibody blockade of IL-10 restored T cell activity and purged the persistent infection, indicating that host regulatory mechanisms actually permit viral persistence and are actively responsible for preventing clearance. This research suggests the exciting prospect that, when freed, T cells are capable of controlling persistent viruses. A better understanding of how immunosuppressive factors inhibit immunity is critical for the design of therapies to re-establish immune control and prevent and potentially eradicate persistent viral infections. In the current proposal I will define the mechanisms leading to IL-10 mediated immunosuppression during persistent viral infection. I will utilize cutting- edge microscopy techniques to directly visualize immunosuppressive cells in vivo and the specific interactions that suppress T cell function and sustain T cell exhaustion. These studies will provide the first in vivo mechanistic insights into how host molecules cause immunosuppression during persistent viral infection. I will then test a novel strategy to enhance T cell immunity and purge a long- lived reservoir of viral replication from an immune privileged site. Once completed this effort will have a direct impact toward our understanding of host-virus interactions, the mechanisms employed to promote viral clearance versus persistence and therapeutically the ability to restore immune function to completely eliminate persistent infection. PUBLIC HEALTH RELEVANCE: Strategies to enhance immune activity to clear persistent viral infections have so far been unsuccessful because it is unclear what is required of the immune response to purge virus once it proceeds past acute infection. The experiments outlined in this proposal will investigate a novel factor required to clear a persistent viral infection. Identification of the mechanisms that sustain immunity will aid in the design of therapies to amplify the immune response to control persistent viral infections